tbuckley/cabot-search huggingface dataset:
P14.13.B DECODING GLIOBLASTOMA: SIM4ULATING TUMOUR MICROENVIRONMENT TO DETECT NOVEL BIOMARKERS USING ORGAN-ON-CHIP MODELS
Authors: C Bayona, T Randelovic, M Wrona, J Salafranca, I Ochoa
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most common malignant primary brain tumour in adults, with a survival rate of 14 months even after current treatment. There are two major limitations in understanding how the tumour works and what markers could facilitate its diagnosis. On the one hand, the great heterogeneity is responsible for the ineffectiveness of treatments. This underlines the importance of developing more complex models that can simulate different elements of the tumour microenvironment of GBM, including hypoxic gradients that lead to the generation of the characteristic necrotic core. On the other hand, the diagnostic techniques currently used have their inherent limitations and entail serious risks for the patients. Therefore, the development of diagnostic markers that allow real-time monitoring of tumour status without posing a very high risk, could improve diagnosis and treatment of patients with GBM. METHODS Our approach consisted on a gas impermeable and pillarless microfluidic device composed of a central chamber, where U-251 MG cells were highly dense seeded in a collagen matrix, and two side channels that provided oxygen and nutrients to the cells. The device was used to generate the necrotic region characteristic of glioblastoma, then, the medium that flowed through the lateral channels in contact with the cells was collected on different days of necrotic core formation and analysed by solid-phase microextraction system coupled with gas chromatography-mass spectrometry. This technique was used to detect the presence of differential volatile organic compounds (VOCs) secreted by tumour cells in different microenvironments. RESULTS The microfluidic device enabled the generation of an in vitro glioblastoma tumour microenvironment characterised by a necrotic zone in the centre of the tumour mass after seven days of cell culture. This allowed the study of VOCs in different microenvironment conditions, and showed that devices with a necrotic core exhibited a much more complex VOC footprint. Among the compounds detected were some types of aldehydes, phenols and nitrogen compounds. Clinical validation of the GBM VOC profile is ongoing. CONCLUSION Our impermeable and pillarless device has allowed us to simulate elements of the tumour microenvironment that are difficult to reproduce with other models, such as central necrotic zones surrounded by cells with nutrient availability. In addition, it offers a promising advance in the characterisation of the metabolic fingerprint of glioblastoma that bring us closer to real-time monitoring of the disease with less invasive methods than those currently used.
P14.06.A GLIOMA ESPIONAGE: UTILIZING CSF PROTEOMICS FOR PHARMACODYNAMIC BIOMARKER DISCOVERY
Authors: C Riviere-Cazaux, L Carlstrom, A Munoz-Casabella, K Andersen, S Ikram, A Warrington, T Burns
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Cerebrospinal fluid (CSF) is emerging as an abundant source of candidate biomarkers, including proteins, for gliomas. Longitudinal CSF access may enable insights into treatment response and resistance. To that end, we have established a growing biobank of CSF samples, many of which have been obtained longitudinally via CSF access devices, such as Ommaya reservoirs, through our ongoing biomarker discovery clinical trials (NCT04692337, 04692324). We have previously presented our initial data demonstrating a conserved proteomic signature of HGG that decreased with resection and increased with recurrence. Since then, samples have been acquired throughout individual patients’ treatments toward our goal of identifying CSF-derived biomarkers of treatment response. MATERIAL AND METHODS CSF samples obtained prior to, during, and throughout treatment underwent global proteomics analysis via the SomaScan® assay by Somalogic, which uses slow off-rate modified aptamers to sensitively detect over 7,000 proteins. Fold-changes for each protein were calculated between different timepoints for each patient and ranked based on the comparison of interest. Comparisons included prior to versus after resection, chemoradiation or adjuvant temozolomide (each with or without pembrolizumab), bevacizumab, and low versus high blood contamination. RESULTS Treatment with pembrolizumab alone resulted in increased IL-23 (5.01x), IL-12 (4.25x), lymphocyte activation gene 3 protein (LAG3) (3.26x), and granzyme A (2.93x). Chemoradiation, with or without pembrolizumab, consistently downregulated NAD kinase, acetyl CoA transferase, and Bcl-2 and upregulated proteins related to neuronal signaling, such as neurexins and cerebellins, in addition to LAG-3, suggesting potential for synergy between chemoradiation and anti-LAG-3 antibodies currently in clinical trials. Interestingly, pembrolizumab and chemoradiation decreased MMP-12 and MMP-9 abundance as compared to chemoradiation alone (0.25x vs. 18.5x; 0.54x vs. 4.99x). Finally, bevacizumab treatment consistently increased VEGF (7.32x), GFAP (3.38x), and MMP-3 (2.99x) abundance, while decreasing the presence of our previously reported plasma-associated protein signature in CSF, suggesting decreased blood-brain barrier disruption. CONCLUSION The global CSF proteome can be longitudinally accessed to evaluate response to standard-of-care and experimental therapies. Further studies are ongoing to identify signatures of therapeutic resistance and to assess the impact of novel immunotherapeutic combinations on the CSF proteome.
JS05.5.A INTRAOPERATIVE MRI-GUIDED RESECTION IS NOT SUPERIOR TO 5-ALA-GUIDANCE IN NEWLY DIAGNOSED GLIOBLASTOMA: A PROSPECTIVE CONTROLLED MULTICENTER CLINICAL TRIAL
Authors: C Roder, W Stummer, J Coburger, M Scherer, P Haas, C von der Brelie, M Kamp, M Löhr, C Hamisch, M Skardelly, T Scholz, S Schipmann, J Rathert, C Brand, A Pala, U Ernemann, F Stockhammer, R Gerlach, P Kremer, R Goldbrunner, R Ernestus, M Sabel, V Rohde, G Tabatabai, P Martus, S Bisdas, O Ganslandt, A Unterberg, C Wirtz, M Tatagiba
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma. MATERIAL AND METHODS This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary endpoint was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of pre- and post-operative MRI with 1mm slices. Secondary endpoints included progression-free (PFS) and overall survival (OS), patient-reported quality of life and clinical parameters. RESULTS We recruited 314 patients with newly diagnosed glioblastomas at eleven German centers. 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm (p=0.79). Incision-suture times (p&amp;lt;0.001) were significantly longer in the iMRI arm (316 vs. 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0cm³) was a significant favorable prognostic factor for PFS (p&amp;lt;0.001) and OS (p=0.048), especially in MGMT unmethylated tumors (p=0.006). CONCLUSION We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.
P03.07.B DOSIMETRIC ACCURACY OF CYBERKNIFE STEREOTACTIC RADIOSURGERY FOR BENIGN PERIOPTIC TUMOR
Authors: K Yoon, C Jeong, M Park, Y Goh, S Kim, B Cho, J Kwak, Y Cho
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The Cyberknife (CK) SRS delivers a highly focused ablative radiation dose to tumors to effectively control tumors with minimized radiation toxicity to surrounding normal tissues. This study aimed to evaluate the dosimetric accuracy of Cyberknife (CK) for benign perioptic tumor using patient specific head phantom. METHODS Patient specific head phantoms was fabricated using a 3D-printer to be dosimetrically equivalent to actual target regions of benign perioptic tumor case treated via Cyberknife radiosurgery. Head phantom QA plan was produced using the original CK contour set (target and optic nerve). The head phantom containing the Gafchromic EBT3 film was irradiated using Cyberknife 6D skull tracking method. The dose distributions calculated by MultiPlan Treatment Planning System (version 5.6) was compared with those measured by film dose using gamma analysis method. After moved rotating (1 degree) and translating (1-5mm) the couch table prior to beam delivery, we checked the 6D skull tracking accuracy according to the beam irradiation. RESULTS Gamma passing rates for the 2%/1 mm and 2%/2 mm criteria was found to be 84.11 ± 2.12% and 93.61±1.39% greater than the acceptance criteria 80% and 90%. The difference between measured and calculated dose to the optic nerve in contact with the tumor was less than 3%. CONCLUSION Dosimetric verification with patient-specific head phantoms could be successfully implemented as the evaluation method for CK perioptic tumor radiosurgery delivery with 6D skull tracking system.
P20.06.B SYSTEMIC CHEMOTHERAPY IN ADULT PATIENTS WITH DIFFUSE MIDLINE GLIOMA H3K27-ALTERED
Authors: G Lombardi, M Simonelli, G Minniti, V Di Nunno, G Cerretti, A Di Muzio, S Asioli, M Antonelli, M Padovan, A Dipasquale, M Corrà, D De Biase, P Persico, M Caccese, A Tosoni, B Fernandes, E Franceschi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Adult Diffuse midline glioma (DMG) is a very rare disease. DMGs are currently treated with radiotherapy and temozolomide even if only a few retrospective studies assessed the impact on survival of these approaches. MATERIAL AND METHODS We carried out a multicentric retrospective study of adult patients with DMG to assess the effective role of concurrent and adjuvant chemotherapy. All patients had a diagnosis of DMG - H3K27 altered. Results Overall we included 27 DMG H3K27 mutated patients with a median age of 40 years (range 20-66). Thalamus was the most frequent location (n =10, 37%). Overall, 16 patients (59.3%) underwent biopsy, 9 partial resections (33.3%), and 2 (7.4%) complete resections. The molecular assessment revealed TP53 as the most frequently altered gene (n = 4, 14.8%) followed by PIK3R (n = 2, 7.4%) and NF1 (n = 2, 7.4%). MGMT was methylated in 4 patients (14.8%). After surgery, 22 patients (81.5%) received postoperative radiation therapy (RT). Moreover, 12 patients received concurrent temozolomide (44.4%) and 11 (40.7%) adjuvant temozolomide. Patients receiving adjuvant temozolomide had a significantly longer overall survival (25.3 vs 10.5 months, HR 0.16, 95% CI 0.1 - 0.8, p= 0.02). Adjuvant temozolomide was confirmed to be associated with improved survival also when adjusted for age, surgery received, or tumor location. Conclusion In this multicentric retrospective study, the treatment with adjuvant temozolomide seems to prolong survival in DMG H3K27 altered patients. Further studies are needed to improve survival in these patients.
P03.01.A “TO BE SMART” IN FOLLOW-UP AFTER CRANIAL RADIOTHERAPY: REPORT OF TWO CASES
Authors: S KAMER, O Kitis, A Acarer, C Eraslan, C Calli, Y Anacak
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Stroke-like Migraine Attacks after Radiation Therapy Syndrome (SMART) is a rare, delayed complication of radiation therapy and its real incidence is unknown. In this study, clinical and treatment features of two cases with clinical and radiological diagnosis of SMART are presented. METHODS Case-1: 49 years old male was diagnosed with grade-3 Oligodendroglioma; after gross total surgery treated with 60 Gy local cranial radiotherapy and temozolomide. Patient presented with acute left-sided weakness and numbness, episodic myoclonic jerking of the left arm and leg, 6 years after treatment. Contrast-enhanced MRI and MR angiography revealed no sign of a recurrent tumor but contrast uptake at right parietooccipital cortical giriform in the lobe of the right temporal lobe on post-contrast images (FLAIR and T1) and an increase in cortical blood volume are observed in perfusion MRI (Figure A-B). The clinical and radiologic diagnosis was SMART syndrome. Pulse dose steroids was planned as the primary treatment, and neurological symptoms was completely disappeared. After 3.5 years of the primary episode, patient re-applied with acute headache, homonymous hemianopsia of the left eye and left sided hemiparesia. Cranial MRI revealed the similar features and after treatment with steroids for 7 days complete radiological and clinical regression was experienced. Case-2: 60 years old female with a right occipital grade-3 oligodendroglioma treated with resection followed by local cranial radiotherapy (60 Gy) and temozolomide chemotherapy. Ten years after the treatment she presented with severe headache, expressive aphasia and homonymous hemianopsia of the left eye. Contrast-enhanced MRI and MR angiography revealed no sign of a recurrent tumor but contrast uptake at right occipital cortical giriform on post-contrast images (FLAIR and T1) and an increase in cortical blood volume are observed in perfusion MRI (Figurec. The diagnosis was SMART syndrome. After one week of steroid treatment she completely recovered. Similar complaints recurred 9 months after the first episode and completely recovered with steroids in one week. Radiological finding disappeared in 2 months. CONCLUSION SMART syndrome represents an acute-onset rare condition which may result in serious consequences if not diagnosed and treated properly. It usualy appears years after cranial radiation therapy. Clinical signs and radiological findings may resemble tumor recurrence and distinction from real tumor progression is essential. Treatment is symptomatic, most patients recover with steroids and radiological signs disappear completely, however SMART episodes may recur during the follow-up which can be treated similarly.
P11.51.B STATUS EPILEPTICUS IN WHO GRADE 2 AND 3 DIFFUSE GLIOMA - PREVALENCE AND PREDICTORS
Authors: H Venugopal, S Berendsen, E van Kessel, T Seute, F S S Leijten, P A Robe, T J Snijders
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Status Epilepticus (SE) is a potentially life-threatening and highly debilitating manifestation of diffuse glioma. Glioma-associated SE has yet been poorly studied; consequently, evidence-based recommendations for clinical management are scarce. Prevalence and predictors of SE might vary across the biomolecular heterogeneity of glioma. We aimed to determine the prevalence of SE in grade 2 and 3 diffuse glioma throughout the disease trajectory, and identify associated baseline determinants (BD) and short-term determinants (STD). MATERIAL AND METHODS We conducted a single-center retrospective cohort-study in a consecutive cohort of patients with WHO grade 2 and 3 glioma, diagnosed between 2010 and 2017. Candidate determinant variables included demographic, clinical and tumor-related variables at first surgery (BD) and epilepsy-associated variables immediately preceding the first SE after diagnosis (STD). Occurrence of BD and STD was correlated to (a) all occurrences of SE and (b) SE with in-hospital treatment separately. A within-patient comparison of STD-frequency between a 30-day hazard period and control period, defined relative to the index-SE, was executed. Univariable and multivariable logistic regression analyses were performed for both BD and STD. RESULTS SE occurred in one third of the total cohort (n=63/197). Nearly 14% had an in-hospital treated SE. We identified several baseline clinical and tumor-related correlates of SE in the univariable analyses, including central, parietal and occipital tumor localization, tumor grade, extent of resection and acute symptomatic seizure occurrence after first surgery. In the multivariable model for all SE, parietal tumor localization and acute symptomatic seizure occurrence after first surgery were associated with an increased risk of SE, whereas baseline Karnofsky Performance Score (KPS) and cognitive disorders were associated with a decreased risk; for in hospital-treated SE, the model was too underpowered for valid analyses. None of the STD were significant predictors of (in-hospital) SE. CONCLUSION One third of patients with grade 2 and 3 diffuse glioma developed a SE at any timepoint after diagnosis. Baseline parietal tumor localization, postsurgical acute symptomatic seizure occurrence, KPS and cognitive status were identified as independent determinants of SE. These explorative findings, if validated, could guide personalized risk stratification, patient counselling and therapeutic decision-making in the clinic.
P07.06.A PATIENT-DERIVED GLIOBLASTOMA MINIATURE AND CANCER STEM CELL SUICIDE-INDUCING NANO-AWAKENER BASED ON IT
Authors: S Yoon, S Baek, S Yoo, E Jo, D Lee, J Shim, R Choi, J Park, J Moon, E Kim, J Chang, J Lee, J Park, H Sung, S Kang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patient-specific anti-tumor therapies can evolve by vitalizing the mother tissue-like cancer niche, cellular profile, genetic signature, and drug responsiveness. This evolution elucidated a key mechanism along with the development of the cancer therapy. The present study aimed to meet these clinical demands by approaching the direct culture of GBM patient tissues with a 1 mm post-punching diameter in a 3D microchannel network chip (“GBM miniature”). MATERIAL AND METHODS Hence, we directly cultured of GBM patient tissue (1 mm diameter) in a microchannel network chip (GBM miniature) to preserve mother tissue-like characteristic signatures and microenvironment. When chemoradiation therapy were administered within 1 day, the responsiveness of the tissue in the chip mirroring the clinical outcomes. The characteristics of migrating cells from GBM miniature were analyzed, and peptides that target these migrating CSCs were searched for. And, by attaching this CSC peptide to the nanovesicle, the therapeutic effect was confirmed in GBM miniature. RESULTS Upon testing within 1 day, the tissue chip reflected patient drug responsiveness as seen in the clinic. As the tissue chip culture was continued, the intact GBM signature was getting lost, and the outward migration of stem cells from the tissue origin increased, indicating a leaving-home effect on the family dismantle. Nanovesicle production using GBM stem cells enabled self-chasing of the cells that escaped the temozolomide effect owing to quiescence. The anti-PTPRZ1 peptide display and temozolomide loading to nanovesicles awaked stem cells from the quiescent stage to death. CONCLUSION This research proposes a GBM patient avatar platform and mechanism-learned nanotherapy for translation.
P02.01.A THE ONGOING WAY TO PROVIDE EVIDENCE OF THE ANCESTRAL FOUNDER CELL TO OVERCOME THERAPEUTIC RESISTANCE IN IDH-WILDTYPE GLIOBLASTOMA
Authors: E Brognaro
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Multiple clinical aspects and accumulating indirect and direct experimental data are providing evidence that the supratentorial brain parenchyma becomes entirely and quiescently micro-infiltrated long before primary tumor bulk growth. Two diffuse micro-infiltrations occur in IDH-wildtype glioblastoma, the first long before primary bulk growth (the only one effective in giving rise to distant relapses) and the second, well known but ineffective, during bulk growth and evolution. Furthermore, they clearly indicate that there are two causes of therapeutic resistance, the second never yet therapeutically challenged. MATERIAL AND METHODS The collection of separate multiregional samples in the tumor bulk enabled us to reconstruct the phylogenetic tree of the primary tumor mass. However, the therapeutic solution to IDH-wildtype glioblastoma lies in the micro-infiltrated brain where the ancestral founder CSCs reside quiescently (they are invariably extinct in the tumor bulk at the time of diagnosis). We are using the four ethical methods, as part of normal glioblastoma surgery, to sample the micro-infiltrated brain parenchyma to identify and deeply characterize the dormant ancestral founder CSCs. RESULTS In the bulk, multiple separated samples allowed us to infer the phylogenetic tree of the tumor as well as driver and passenger events and the CSC variants. The ethical methods to sample the micro-infiltrated brain parenchyma are enabling us to identify and characterize the ancestral founder CSCs, which hibernate in the perivascular parenchymal niches of the supratentorial brain (their activation being the only cause of distant recurrences). CONCLUSION The first cause of therapeutic resistance is due to intratumor heterogeneity and the second to the silent presence in the whole supratentorial brain of quiescent founder CSCs. The IDH-wildtype glioblastoma is the only brain tumor that arises from the III layer of the SVZ and it is able to disseminate widely across the supratentorial brain parenchyma before starting its growth. Only the identification and characterization of the ancestral founder CSC will enable us to simultaneously overcome both causes of resistance and provide a therapeutic solution to this dreadful malignancy. Indeed, the ancestral founder CSC is identical to the premalignant progenitor of the SVZ and to the cell that activated in one (or more) brain location, gave rise to the primary tumor bulk(s) and transmitted the ancestral driver genomic alterations to all subsequent evolutionary CSC variants.